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Microbiology Spectrum Jun 2024is one of the most important pathogens worldwide. The intrinsic and acquired resistance of , coupled with the slow pace of novel antimicrobial drug development, poses...
UNLABELLED
is one of the most important pathogens worldwide. The intrinsic and acquired resistance of , coupled with the slow pace of novel antimicrobial drug development, poses an unprecedented and enormous challenge to clinical anti-infective therapy of . Recent studies in the field of pathogenicity, antibiotic resistance, and biofilms of have focused on the model strains, including ATCC 17978, ATCC 19606, and AB5075. However, these model strains represent only a limited portion of the heterogeneity in . Furthermore, variants of these model strains have emerged that show significant diversity not only at the genotypic level but also reflected in differences at the phenotypic levels of capsule, virulence, pathogenicity, and antibiotic resistance. Research on , a key pathogen, would benefit from a standardized approach, which characterizes heterogeneous strains in order to facilitate rapid diagnosis, discovery of new therapeutic targets, and efficacy assessment. Our study provides and describes a standardized, genomically and phenotypically heterogeneous panel of 45 different strains for the research community. In addition, we performed comparative analyses of several phenotypes of this panel. We found that the sequence type 2 (ST2) group showed significantly higher rates of resistance, lower fitness cost for adaptation, and yet less biofilm formation. The Macrocolony type E (MTE, flat center and wavy edge phenotype reported in the literature) group showed a less clear correlation of resistance rates and growth rate, but was observed to produce more biofilms. Our study sheds light on the complex interplay of resistance fitness and biofilm formation within distinct strains, offering insights crucial for combating infection.
IMPORTANCE
is globally notorious, and in an effort to combat the spread of such pathogens, several emerging candidate therapies have already surfaced. However, the strains used to test these therapies vary across studies (the sources and numbers of test strains are varied and often very large, with little heterogeneity). The variation complicates the studies. Furthermore, the limited standardized resources of strains have greatly restricted the research on the physiology, pathogenicity, and antibiotic resistance. Therefore, it is crucial for the research community to acquire a standardized and heterogeneous panel of . Our study meticulously selected 45 diverse strains from a total of 2,197 clinical isolates collected from 64 different hospitals across 27 provinces in China, providing a scientific reference for the research community. This assistance will significantly facilitate scientific exchange in academic research.
PubMed: 38916336
DOI: 10.1128/spectrum.00086-24 -
Drug Design, Development and Therapy 2024Remimazolam besylate is a novel ultra-short-acting benzodiazepine that is rapidly hydrolyzed to zolpidem propionic acid by tissue lipases. We designed this study to... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Comparison of the Safety and Efficacy of Remimazolam Besylate versus Dexmedetomidine for Patients Undergoing Fiberoptic Bronchoscopy: A Prospective, Randomized Controlled Trial.
OBJECTIVE
Remimazolam besylate is a novel ultra-short-acting benzodiazepine that is rapidly hydrolyzed to zolpidem propionic acid by tissue lipases. We designed this study to compare the safety and efficacy of remimazolam besylate alfentanil versus dexmedetomidine-alfentanil for fiberoptic bronchoscopy (FB).
METHODS
One hundred and twenty patients undergoing FB into this prospective randomized controlled trial were divided into two groups. The anesthesia induction consisted of 6 mg/kg/h of remimazolam besylate in the RA group and 0.5 μg/kg of dexmedetomidine in the DA group. 1-2 mg/kg/h of remimazolam besylate or 0.2-0.7 µg/kg/h of dexmedetomidine were administered to maintain during FB. The lowest oxygen saturation, success rate of FB, hemodynamics, time metrics, bronchoscopy feasibility, drug dose requirements, patient and bronchoscopist satisfaction scores, occurrence of intraoperative awareness, number of patients willing to repeat FB with the same sedation regimen, and occurrence and severity of adverse events.
RESULTS
The lowest oxygen saturation during the FB was significantly higher in the RA group ( = 0.001). Compared with the variables in the DA group, peripheral oxygen saturation, systolic blood pressure, and diastolic blood pressure were significantly lower at T2 and T3 in the RA group ( < 0.05). Heart rates were significantly higher from T2 to T4 in the DA group ( < 0.05). More patients experienced bradycardia in the DA group ( = 0.041). Compared with time metrics in the DA group, the induction time, fully-alert time, and recovery room-leaving time were all significantly shorter in the RA group ( < 0.05). The bronchoscopy feasibility scores in the RA group were significantly lower at T2, whereas they were lower at T3 in the DA group ( < 0.05).
CONCLUSION
Remimazolam besylate is superior to dexmedetomidine when combined with alfentanil during FB, promoting faster patients' recovery, better operative conditions and respiratory stability with similar rates of occurrence and severity of adverse events.
Topics: Humans; Dexmedetomidine; Bronchoscopy; Prospective Studies; Male; Female; Middle Aged; Adult; Benzodiazepines; Hypnotics and Sedatives; Aged
PubMed: 38915861
DOI: 10.2147/DDDT.S460949 -
BioRxiv : the Preprint Server For... Jun 2024The transmission bottleneck, defined as the number of viruses that transmit from one host to infect another, is an important determinant of the rate of virus evolution...
The transmission bottleneck, defined as the number of viruses that transmit from one host to infect another, is an important determinant of the rate of virus evolution and the level of immunity required to protect against virus transmission. Despite its importance, SARS-CoV-2's transmission bottleneck remains poorly characterized, in part due to a lack of quantitative measurement tools. To address this, we adapted a SARS-CoV-2 reverse genetics system to generate a pool of >200 isogenic SARS-CoV-2 viruses harboring specific 6-nucleotide barcodes inserted in ORF10, a non-translated ORF. We directly inoculated donor Syrian hamsters intranasally with this barcoded virus pool and exposed a paired naïve contact hamster to each donor. Following exposure, the nasal turbinates, trachea, and lungs were collected, viral titers were measured, and the number of barcodes in each tissue were enumerated to quantify the transmission bottleneck. The duration and route (airborne, direct contact, and fomite) of exposure were varied to assess their impact on the transmission bottleneck. In airborne-exposed hamsters, the transmission bottleneck increased with longer exposure durations. We found that direct contact exposure produced the largest transmission bottleneck (average 27 BCs), followed by airborne exposure (average 16 BCs) then fomite exposure (average 8 BCs). Interestingly, we detected unique BCs in both the upper and lower respiratory tract of contact animals from all routes of exposure, suggesting that SARS-CoV-2 can directly infect hamster lungs. Altogether, these findings highlight the utility of barcoded viruses as tools to rigorously study virus transmission. In the future, barcoded SARS-CoV-2 will strengthen studies of immune factors that influence virus transmission.
PubMed: 38915710
DOI: 10.1101/2024.06.08.597602 -
Journal of Korean Medical Science Jun 2024Antimicrobial resistance (AMR) is an important global public health concern in adults and children. Laryngotracheobronchitis (croup) is a common acute respiratory...
BACKGROUND
Antimicrobial resistance (AMR) is an important global public health concern in adults and children. Laryngotracheobronchitis (croup) is a common acute respiratory infection (ARI) among children, most often caused by a virus, and should not be treated with antibiotics. Reducing the usage of unnecessary antibiotics in ARI using an antimicrobial stewardship program (ASP) is an effective measure against AMR in children. This study investigates the antibiotic prescription pattern in pediatric patients with laryngotracheobronchitis in Korea. Our results will be useful to improve the ASP.
METHODS
The data were obtained from the government agency Health Insurance Review and Assessment Service. We analyzed outpatient prescriptions issued to children ≤ 5 years of age with a first-listed diagnosis code for laryngotracheobronchitis, i.e., International Classification of Disease, 10th Revision, code J050 (croup), J040 (laryngitis), or J041 (tracheitis), during 2017-2020. For each prescription, demographic information and information about medical facilities visited (type of hospital, specialty of physician, location of hospital) were extracted. The overall antibiotic prescription rate was subsequently estimated, and multivariable analysis was conducted to determine the associated factors of antibiotic prescription. Prescribed antibiotics were described and classified into extended-spectrum penicillins, cephalosporin, and macrolides.
RESULTS
Of 2,358,194 prescriptions reviewed, 829,172 (35.2%) contained antibiotics. In the multivariable analysis, management in a hospital was the strongest factor associated with antibiotic prescription (adjusted odds ratio [aOR], 22.33; 95% confidence interval [CI], 20.87-23.89; < 0.001), followed by management in a clinic (aOR, 12.66; 95% CI, 11.83-13.54; < 0.001) and management in a general hospital (aOR, 8.96; 95% CI, 8.37-9.59; < 0.001). Antibiotic prescription was also significantly associated with patients who were ≤ 2 years of age, managed by a pediatric specialist, and treated at a hospital located in a non-metropolitan region. Overall, extended-spectrum penicillins were the most frequently prescribed (18.6%) antibiotics, followed by cephalosporins (9.4%) and macrolides (8.5%).
CONCLUSION
The results of our study suggest that ASPs need to focus on physicians in hospitals, clinics, general hospitals, and pediatric specialties. Providing education programs to these groups to increase awareness of AMR and appropriate antibiotics use could be effective ASP policy and may help to reduce unnecessary prescriptions of antibiotics for laryngotracheobronchitis among pediatric patients and therefore potentially AMR in children in Korea.
Topics: Humans; Anti-Bacterial Agents; Republic of Korea; Child, Preschool; Infant; Male; Female; Tracheitis; Antimicrobial Stewardship; Laryngitis; Practice Patterns, Physicians'; Bronchitis; Infant, Newborn; Drug Prescriptions; Croup
PubMed: 38915281
DOI: 10.3346/jkms.2024.39.e189 -
Pneumonia (Nathan Qld.) Jun 2024There exists consistent empirical evidence in the literature pointing out ample heterogeneity in terms of the clinical evolution of patients with COVID-19. The...
BACKGROUND
There exists consistent empirical evidence in the literature pointing out ample heterogeneity in terms of the clinical evolution of patients with COVID-19. The identification of specific phenotypes underlying in the population might contribute towards a better understanding and characterization of the different courses of the disease. The aim of this study was to identify distinct clinical phenotypes among hospitalized patients with SARS-CoV-2 pneumonia using machine learning clustering, and to study their association with subsequent clinical outcomes as severity and mortality.
METHODS
Multicentric observational, prospective, longitudinal, cohort study conducted in four hospitals in Spain. We included adult patients admitted for in-hospital stay due to SARS-CoV-2 pneumonia. We collected a broad spectrum of variables to describe exhaustively each case: patient demographics, comorbidities, symptoms, physiological status, baseline examinations (blood analytics, arterial gas test), etc. For the development and internal validation of the clustering/phenotype models, the dataset was split into training and test sets (50% each). We proposed a sequence of machine learning stages: feature scaling, missing data imputation, reduction of data dimensionality via Kernel Principal Component Analysis (KPCA), and clustering with the k-means algorithm. The optimal cluster model parameters -including k, the number of phenotypes- were chosen automatically, by maximizing the average Silhouette score across the training set.
RESULTS
We enrolled 1548 patients, each of them characterized by 92 clinical attributes (d=109 features after variable encoding). Our clustering algorithm identified k=3 distinct phenotypes and 18 strongly informative variables: Phenotype A (788 cases [50.9% prevalence] - age 57, Charlson comorbidity 1, pneumonia CURB-65 score 0 to 1, respiratory rate at admission 18 min, FiO 21%, C-reactive protein CRP 49.5 mg/dL [median within cluster]); phenotype B (620 cases [40.0%] - age 75, Charlson 5, CURB-65 1 to 2, respiration 20 min, FiO 21%, CRP 101.5 mg/dL); and phenotype C (140 cases [9.0%] - age 71, Charlson 4, CURB-65 0 to 2, respiration 30 min, FiO 38%, CRP 152.3 mg/dL). Hypothesis testing provided solid statistical evidence supporting an interaction between phenotype and each clinical outcome: severity and mortality. By computing their corresponding odds ratios, a clear trend was found for higher frequencies of unfavourable evolution in phenotype C with respect to B, as well as more unfavourable in phenotype B than in A.
CONCLUSION
A compound unsupervised clustering technique (including a fully-automated optimization of its internal parameters) revealed the existence of three distinct groups of patients - phenotypes. In turn, these showed strong associations with the clinical severity in the progression of pneumonia, and with mortality.
PubMed: 38915125
DOI: 10.1186/s41479-024-00132-0 -
Resuscitation Plus Sep 2024Rapid response team or medical emergency team (MET) calls are typically activated by significant alterations of vital signs in inpatients. However, the clinical...
BACKGROUNDS
Rapid response team or medical emergency team (MET) calls are typically activated by significant alterations of vital signs in inpatients. However, the clinical significance of a specific criterion, blood pressure elevations, is uncertain.
OBJECTIVES
The aim of this study was to evaluate the likelihood ratios associated with MET-activating vital signs, particularly in-patient hypertension, for predicting in-hospital mortality among general medicine inpatients who met MET criteria at any point during admission in a South Australian metropolitan teaching hospital.
RESULTS
Among the 15,734 admissions over a two-year period, 4282 (27.2%) met any MET criteria, with a positive likelihood ratio of 3.05 (95% CI 2.93 to 3.18) for in-hospital mortality. Individual MET criteria were significantly associated with in-hospital mortality, with the highest positive likelihood ratio for respiratory rate ≤ 7 breaths per minute (9.83, 95% CI 6.90 to 13.62), barring systolic pressure 200 mmHg (LR + 1.26, 95% CI 0.86 to 1.69).
CONCLUSIONS
Our results show that meeting the MET criteria for hypertension, unlike other criteria, was not significant associated with in-hospital mortality. This observation warrants further research in other patient cohorts to determine whether blood pressure elevations should be routinely included in MET criteria.
PubMed: 38912533
DOI: 10.1016/j.resplu.2024.100679 -
Journal of Inflammation Research 2024Research on biomarkers associated with the severity and adverse prognosis of COVID-19 can be beneficial for improving patient outcomes. However, there is limited...
BACKGROUND
Research on biomarkers associated with the severity and adverse prognosis of COVID-19 can be beneficial for improving patient outcomes. However, there is limited research on the role of soluble TREM-1 (sTREM-1) in predicting the severity and prognosis of COVID-19 patients.
METHODS
A total of 115 COVID-19 patients admitted to the emergency department of Beijing Youan Hospital from February to May 2023 were included in the study. Demographic information, laboratory measurements, and blood samples for sTREM-1 levels were collected upon admission.
RESULTS
Our study found that sTREM-1 levels in the plasma of COVID-19 patients increased with the severity of the disease (moderate vs mild, p=0.0013; severe vs moderate, p=0.0195). sTREM-1 had good predictive value for disease severity and 28-day mortality (area under the ROC curve was 0.762 and 0.805, respectively). sTREM-1 also exhibited significant correlations with age, body temperature, respiratory rate, PaO/FiO, PCT, CRP, and CAR. Ultimately, through multivariate logistic regression analysis, we determined that sTREM-1 (OR 1.008, 95% CI: 1.002-1.013, p=0.005), HGB (OR 0.966, 95% CI: 0.935-0.998, p=0.036), D-dimer (OR 1.001, 95% CI: 1.000-1.001, p=0.009), and CAR (OR 1.761, 95% CI: 1.154-2.688, p=0.009) were independent predictors of 28-day mortality in COVID-19 patients. The combination of these four markers yielded a strong predictive value for 28-day mortality in COVID-19 cases with an AUC of 0.919 (95% CI: 0.857 -0.981).
CONCLUSION
sTREM-1 demonstrated good predictive value for disease severity and 28-day mortality, serving as an independent prognostic factor for adverse patient outcomes. In the future, we anticipate conducting large-scale multicenter studies to validate our research findings.
PubMed: 38911986
DOI: 10.2147/JIR.S464789 -
Open Life Sciences 2024Adverse cardiac mechanical remodeling is critical for the progression of heart failure following myocardial infarction (MI). We previously demonstrated the involvement...
Adverse cardiac mechanical remodeling is critical for the progression of heart failure following myocardial infarction (MI). We previously demonstrated the involvement of RIP3-mediated necroptosis in the loss of functional cardiomyocytes and cardiac dysfunction post-MI. Herein, we investigated the role of RIP3 in NOD-like receptor protein 3 (NLRP3)-mediated inflammation and evaluated the effects of RIP3 knockdown on myocardial mechanics and functional changes after MI. Our findings revealed that mice with MI for 4 weeks exhibited impaired left ventricular (LV) myocardial mechanics, as evidenced by a significant decrease in strain and strain rate in each segment of the LV wall during both systole and diastole. However, RIP3 knockdown ameliorated cardiac dysfunction by improving LV myocardial mechanics not only in the anterior wall but also in other remote nonischemic segments of the LV wall. Mechanistically, knockdown of RIP3 effectively inhibited the activation of the nuclear factor kappa-B (NF-κB)/NLRP3 pathway, reduced the levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in the heart tissues, and mitigated adverse cardiac remodeling following MI. These results suggest that downregulation of RIP3 holds promise for preventing myocardial inflammation and cardiac mechanical remodeling following MI by regulating the NF-κB/NLRP3 pathway.
PubMed: 38911926
DOI: 10.1515/biol-2022-0890 -
Annals of Translational Medicine Jun 2024Advancements in medical technologies have led to the development of contact-free methods of haemodynamic monitoring such as remote photoplethysmography (rPPG). rPPG uses...
BACKGROUND
Advancements in medical technologies have led to the development of contact-free methods of haemodynamic monitoring such as remote photoplethysmography (rPPG). rPPG uses video cameras to interpret variations in skin colour related to blood flow, which are analysed to generate vital signs readings. rPPG potentially ameliorates problems like fretfulness and fragile skin contact associated with conventional probes in children. While rPPG has been validated in adults, no prior validation has been performed in children.
METHODS
A two-phased prospective cross-sectional single-centre study was conducted from January to April 2023 to evaluate the feasibility, acceptability, and accuracy of obtaining heart rate (HR), respiratory rate (RR) and oxygen saturation (SpO) using rPPG in children, compared to the current standard of care. In Phase 1, we recruited patients ≤16 years from the neonatal and paediatric wards. We excluded preterm neonates with gestational age <35 weeks and newborns <24 hours old. The rPPG webcam was positioned 30 cm from the face. After 1 minute of facial scanning, readings generated were compared with pulse oximetry for HR and SpO, and manual counting for RR. Correlation and Bland-Altman analyses were performed. In Phase 2, we focused on the population in whom there was potential correlation between rPPG and the actual vital signs.
RESULTS
Ten neonates and 28 children aged 5 to 16 years were recruited for Phase 1 (765 datapoints). All patients were haemodynamically stable and normothermic. Patients and caregivers showed high acceptability to rPPG. rPPG values were clinically discrepant for children <10 years. For those ≥10 years, moderate correlation was observed for HR, with Spearman's correlation coefficient (Rs) of 0.50 [95% confidence intervals (CI): 0.42, 0.57]. We performed Phase 2 on 23 patients aged 12 to 16 years (559 datapoints). Strong correlation was observed for HR with Rs=0.82 (95% CI: 0.78, 0.85). There was weak correlation for SpO and RR (Rs=-0.25 and -0.02, respectively).
CONCLUSIONS
Our study showed that rPPG is acceptable and feasible for neonates and children aged 5 to 16 years, and HR values in older children aged 12 to 16 years correlated well with the current standard. The rPPG algorithms need to be further refined for younger children, and for obtaining RR and SpO in all children. If successful, rPPG will provide a viable contact-free alternative for assessing paediatric vital signs, with potential use in remote monitoring and telemedicine.
PubMed: 38911566
DOI: 10.21037/atm-23-1896 -
RSC Medicinal Chemistry Jun 2024Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of coronavirus disease (COVID-19) since its emergence in December 2019. As of...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of coronavirus disease (COVID-19) since its emergence in December 2019. As of January 2024, there has been over 774 million reported cases and 7 million deaths worldwide. While vaccination efforts have been successful in reducing the severity of the disease and decreasing the transmission rate, the development of effective therapeutics against SARS-CoV-2 remains a critical need. The main protease (Mpro) of SARS-CoV-2 is an essential enzyme required for viral replication and has been identified as a promising target for drug development. In this study, we report the identification of novel Mpro inhibitors, using a combination of deep reinforcement learning for drug design with 3D pharmacophore/shape-based alignment and privileged fragment match count scoring components followed by hit expansions and molecular docking approaches. Our experimentally validated results show that 3 novel series exhibit potent inhibitory activity against SARS-CoV-2 Mpro, with IC values ranging from 1.3 μM to 2.3 μM and a high degree of selectivity. These findings represent promising starting points for the development of new antiviral therapies against COVID-19.
PubMed: 38911172
DOI: 10.1039/d4md00106k